Objectives: To evaluate the involvement of NR2E3 in inherited retinal degenerative diseases in the Israeli and Palestinian populations and to study phenotypic variability in patients who are homozygous for the same mutation.
Methods: Patients from 35 families underwent clinical evaluation, including a full ophthalmologic examination and electroretinography. Genetic analyses included direct sequencing of polymerase chain reaction products and haplotype reconstruction.
Results: We recruited 6 consanguineous Muslim families and 2 Jewish families with enhanced S-cone syndrome. Patients from 4 of the Muslim families were homozygous for the same NR2E3 mutation, c.119-2A>C, but showed considerable variability in fundus appearance and retinal function, even among patients of comparable ages. Both Jewish patients were compound heterozygotes for the c.932G>A mutation in combination with c.194-202del9bp or a novel splice-site mutation, c.747+1G>C. Homozygosity analysis in 27 consanguineous families with retinitis pigmentosa revealed a homozygous mutation, c.932G>A, in 2 families. The electroretinographic responses in these patients were compatible with retinitis pigmentosa and did not show the characteristic enhanced S-cone syndrome pattern.
Conclusion: Our results demonstrate the involvement of NR2E3 in enhanced S-cone syndrome and retinitis pigmentosa phenotypes in our populations.
Clinical relevance: Patients with NR2E3 mutations may manifest variable phenotypes. Moreover, patients who are homozygous for the same NR2E3 mutation have variable expression of retinal disease, suggesting the involvement of modifier genes.